US2003191066A1PendingUtilityA1

Enone cancer therapeutics

Assignee: CORNELL RES FOUNDATION INCPriority: Mar 15, 2002Filed: Mar 15, 2002Published: Oct 9, 2003
Est. expiryMar 15, 2022(expired)· nominal 20-yr term from priority
A61K 31/56A61K 38/00C07K 5/0215
48
PatentIndex Score
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Claims

Abstract

New enone derivatives and conjugates are described. These compounds can be used as cancer therapeutics.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A composition comprising an enone selected from the following group, stereoisomers thereof, and positional isomers thereof  
       
         
           
           
               
               
           
         
       
       wherein X is a nucleophilic atom selected from the group consisting of S, N, and O and R is selected from the group consisting of OCOCH=CHCH 3 , OCOCH 3 , OCOC 6 H 5 , OCONHCH 3 , estrogen, testosterone, sex hormone steroids, and therapeutically effective derivatives of sex hormone steroids.  
     
     
         2 . The enone of  claim 1  comprising a derived glutathione adduct.  
     
     
         3 . The derived glutathione adduct of  claim 2  wherein said glutathione adduct is produced by the action of glutathionyl transferase.  
     
     
         4 . The enone of  claim 1  wherein the therapeutically effective derivatives of sex hormone steroids comprise estradiol conjugates selected from the following group, stereoisomers thereof, and positional isomers thereof  
       
         
           
           
               
               
           
         
       
     
     
         5 . The enone of  claim 1  wherein the therapeutically effective derivatives of sex hormone steroids comprise testosterone conjugates selected from the following group, stereoisomers thereof, and positional isomers thereof  
       
         
           
                 
                 
                 
               
                     
                 
                     
                 
                     
                     
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   15 R′ = H, R = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   16 R′ = H, R = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   17 R = H, R′ = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   18 R = H, R′ = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         6 . The enone of  claim 1  comprising a polymeric substance wherein the enone is bound to water-soluble copolymers.  
     
     
         7 . The enone of  claim 6  wherein the water-soluble copolymers comprise N-(2-hydroxypropyl) methacrylamide copolymers.  
     
     
         8 . Cancer therapeutics comprising reactive compounds conjugated to tumor-targeting moieties, such cancer therapeutics being transformed intracellularly by the nucleophilic addition of reduced glutathione to then have their therapeutic effect by reacting, in turn, with cancer cell proteins or nucleic acids.  
     
     
         9 . A cancer therapeutic comprising an enone selected from following group, stereoisomers thereof, and positional isomers thereof  
       
         
           
           
               
               
           
         
       
       wherein X is a nucleophilic atom selected from the group consisting of S, N, and O and R is selected from the group consisting of OCOCH=CHCH 3 , OCOCH 3 , OCOC 6 H 5 , OCONHCH 3 , estrogen, testosterone, sex hormone steroids, and therapeutically effective derivatives of sex hormone steroids.  
     
     
         10 . The cancer therapeutic of  claim 9  comprising a derived glutathione adduct.  
     
     
         11 . The derived glutathione adduct of  claim 10  wherein said glutathione adduct is produced by the action of glutathionyl transferase.  
     
     
         12 . The cancer therapeutic of  claim 9  wherein the therapeutically effective derivatives of sex hormone steroids comprise estradiol conjugates selected from the following group, stereoisomers thereof, and positional isomers thereof  
       
         
           
           
               
               
           
         
       
     
     
         13 . The cancer therapeutic of  claim 9  wherein the therapeutically effective derivatives of sex hormone steroids comprise testosterone conjugates selected from the following group, stereoisomers thereof, and positional isomers thereof  
       
         
           
                 
                 
                 
               
                     
                 
                     
                 
                     
                     
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   15 R′ = H, R = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   16 R′ = H, R = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   17 R = H, R′ = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   18 R = H, R′ = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         14 . The cancer therapeutic of  claim 9  comprising a polymeric substance wherein the cancer therapeutic is bound to water-soluble copolymers.  
     
     
         15 . The cancer therapeutic of  claim 14  wherein the water-soluble copolymers comprise N-(2-hydroxypropyl) methacrylamide copolymers.  
     
     
         16 . The cancer therapeutic of  claim 9  comprising a pharmaceutical composition.  
     
     
         17 . The cancer therapeutic of  claim 16  comprising physiologically acceptable formulation agents.  
     
     
         18 . The cancer therapeutic of  claim 16  wherein said cancer therapeutic is delivered intravenously.  
     
     
         19 . The cancer therapeutic of  claim 16  wherein said cancer therapeutic is delivered orally.  
     
     
         20 . The cancer therapeutic of  claim 16  comprising a combination therapeutic.  
     
     
         21 . The cancer therapeutic of  claim 20  wherein the components of the combination therapeutic are delivered at the same time.  
     
     
         22 . The cancer therapeutic of  claim 20  wherein the components of the combination therapeutic are delivered at different times.  
     
     
         23 . The cancer therapeutic of  claim 20  wherein the components of the combination therapeutic are delivered intravenously.  
     
     
         24 . The cancer therapeutic of  claim 20  wherein the components of the combination therapeutic are delivered orally.  
     
     
         25 . The cancer therapeutic of  claim 20  wherein the components of the combination therapeutic are delivered by different methods.  
     
     
         26 . A method for treating cancer comprising the administration of a therapeutically effective amount of an enone selected from the following group, stereoisomers thereof, and positional isomers thereof  
       
         
           
           
               
               
           
         
       
       wherein X is a nucleophilic atom selected from the group consisting of S, N, and O and R is selected from the group consisting of OCOCH=CHCH 3 , OCOCH 3 , OCOC 6 H 5 , OCONHCH 3 , estrogen, testosterone, sex hormone steroids, and therapeutically active derivatives of sex hormone steroids.  
     
     
         27 . The enone of  claim 26  comprising a derived glutathione adduct.  
     
     
         28 . The derived glutathione adduct of  claim 26  wherein said glutathione adduct is produced by the action of glutathionyl transferase.  
     
     
         29 . The method of  claim 26  wherein the therapeutically effective derivatives of sex hormone steroids comprise estradiol conjugates selected from the following group, stereoisomers thereof, and positional isomers thereof  
       
         
           
           
               
               
           
         
       
     
     
         30 . The method of  claim 26  wherein the therapeutically effective derivatives of sex hormone steroids comprise testosterone conjugates selected from the following group, stereoisomers thereof, and positional isomers thereof  
       
         
           
                 
                 
                 
               
                     
                 
                     
                 
                     
                     
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   15 R′ = H, R = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   16 R′ = H, R = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   17 R = H, R′ = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   18 R = H, R′ = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         31 . The method of  claim 26  wherein the enone comprises a polymeric substance in which the enone is bound to water-soluble copolymers.  
     
     
         32 . The method of  claim 31  wherein the water-soluble copolymers comprise N-(2-hydroxypropyl) methacrylamide copolymers.  
     
     
         33 . The method of  claim 26  wherein the enone comprises a physiologically acceptable pharmaceutical formulation.  
     
     
         34 . The method of  claim 33  wherein the mode of delivery of the enone is intravenous.  
     
     
         35 . The method of  claim 33  wherein the mode of delivery of the enone is oral.  
     
     
         36 . The method of  claim 33  wherein the enone is delivered as part of a combination cancer therapeutic.  
     
     
         37 . The method of  claim 36  wherein the components of the combination cancer therapeutic are delivered at the same time.  
     
     
         38 . The method of  claim 36  wherein the components of the combination cancer therapeutic are delivered at different times.  
     
     
         39 . The method of  claim 36  wherein the components of the combination cancer therapeutic are delivered intravenously.  
     
     
         40 . The method of  claim 36  wherein the components of the combination cancer therapeutic are delivered orally.  
     
     
         41 . The method of  claim 36  wherein the components of the combination cancer therapeutic are delivered by different methods.  
     
     
         42 . A method of making a glutathione adduct comprising: 
 a) selecting an enone from the following group, stereoisomers thereof, and positional isomers thereof                          wherein X is a nucleophilic atom selected from the group consisting of S, N, and O and R is selected from the group consisting of OCOCH=CHCH 3 , OCOCH 3 , OCOC 6 H 5 , OCONHCH 3 , estrogen, testosterone, sex hormone steroids, and therapeutically effective derivatives of sex hormone steroids; and    b) reacting said enone with glutathionyl transferase.    
     
     
         43 . The method of  claim 42  wherein the therapeutically effective derivatives of sex hormone steroids comprise estradiol conjugates selected from the following group, stereoisomers thereof, and positional isomers thereof  
       
         
           
           
               
               
           
         
       
     
     
         44 . The enone of  claim 42  wherein the therapeutically effective derivatives of sex hormone steroids comprise testosterone conjugates selected from the following group, stereoisomers thereof, and positional isomers thereof  
       
         
           
                 
                 
                 
               
                     
                 
                     
                 
                     
                     
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   15 R′ = H, R = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   16 R′ = H, R = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   17 R = H, R′ = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   18 R = H, R′ = 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         45 . The enone of  claim 42  comprising a polymeric substance wherein the enone is bound to water-soluble copolymers.  
     
     
         46 . The enone of  claim 45  wherein the water-soluble copolymers comprise N-(2-hydroxypropyl) methacrylamide copolymers.  
     
     
         47 . A method of treating cancer comprising: 
 a) delivering reactive compounds conjugated to tumor-targeting moieties into an individual;    b) allowing said reactive compounds conjugated to tumor-targeting moieties to be transformed intracellularly by the nucleophilic addition of reduced glutathione; and    c) allowing said transformed reactive compounds to then have their therapeutic effect by reacting, in turn, with cancer cell proteins or nucleic acids.

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